We propose to extend our developments with magnetic resonance imaging (MRI) for tracking neuronal fibers in the lining human brain. The method, called diffusion tensor tracking (DTT), reconstructs continuous threedimensional trajectories of neuronal fiber bundles from diffusion tensor-encoded MRI data (DT-MRI). Compared to other methods, the MR procedure is non-invasive, capable of studying connectional anatomy unique to humans, and amenable to direct correlation with fMRI activations in the same individual subjects, which potentially will uncover the neuronal connections used for human tasks. Noninvasive DTT methods are especially important for revealing connections in humans associated with cognitive functions like language that cannot be extrapolated from non-human primate studies. For Aim I we will further enhance current computations of three- dimensional whole-brain fiber trajectories from DT-MRI data and develop and refine methods for selecting different fiber groups, especially including connections between regions defined by fMRI. For Aim II we will evaluate the accuracy and precision of DTT fiber trajectories by computer simulation and test-retest evaluation of experimental data. In Aim III we will assess the ability of DTT to determine the connectivity between fMRI-defined primary sensory and higher-order regions in the somatosensory and visual systems using known monkey neuroanatomy as a standard. The visual studies will involve retinotopic fMRI mapping to identify higher visual areas and to select functional subsets of the geniculocalcarine tract, and motion perception studies to activate remote cognitive regions outside the visual cortex. For Aim IV we will examine the potential clinical utility of DTT to characterize the functional effects of white matter lesions by correlating the lesion-to-cortex DTT projections with cortical defects in retinotopic fMRI and with visual field defects in patients with focal lesions of the geniculocalcarine tract. In Aim V, we will compare visual cortex connections in sighted, early- and late-blind subjects to assess the effects of age of blindness on the development and organization of the visual system. Successful completion of the proposed research will provide a set of tested tools for interrogating the development, functional organization, and reorganization of the human brain in normal and disease.